EP2155763A1

EP2155763A1 - Method for synthesizing cyclohexyl-substituted phosphines

Info

Publication number: EP2155763A1
Application number: EP08750169A
Authority: EP
Inventors: Alexander Tishkov; Klemens Massonne; Daniela Mirk; Jochem Henkelmann; Matthias Maase; Thomas Wettling
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2007-05-08
Filing date: 2008-05-07
Publication date: 2010-02-24
Also published as: WO2008135594A1; US20100137643A1

Abstract

The present invention relates to a method for synthesizing cyclohexyl-substituted phosphines. In addition, the invention relates to a method for synthesizing cyclohexyl-substituted phosphine oxides which can be used as intermediate products in the synthesis of cyclohexyl-substituted phosphines of Formula (I), in which R represents a group of Formula (II), or a linear or branched alkyl group with 1 to 8 carbon atoms, which carries the 1, 2, 3, or 4 groups of Formula (III) and which may carry, in addition, 1 to 4 substituents of Formula (IV); X and Y independently represent O or NR<SUP>8</SUP>.

Description

Process for the preparation of cyclohexyl-substituted phosphines

description

The present invention relates to a process for the preparation of cyclohexyl-substituted phosphines. Moreover, the invention relates to a process for the preparation of cyclohexyl-substituted phosphine oxides, which can be used as intermediates in the preparation of cyclohexyl-substituted phosphines.

Cyclohexyl-substituted phosphines, such as tricyclohexylphosphine, ring-hydrogenated DIOP, or nucleus-hydrogenated chiraphos, are important ligands that have been used in numerous reactions, e.g. in metathesis reactions, carbonylation reactions and Suzuki couplings.

So far, the preparation of cyclohexyl-substituted phosphines is usually carried out from the Cylohexyl- and phosphine basic building blocks or by nuclear hydrogenation of the corresponding phenyl-substituted phosphines.

For example, tricyclohexylphosphine is predominantly formed by reaction of phosphorus trichloride with a cyclohexylmagnesium halide, as described, for example, in Z. Anorg. AIIg. Chem. 277, 1954, 258 or in Chem. Ber. 95, 1962, 1894. Disadvantages here are the handling of the reactants, which is not unproblematic, as is the case with all magnesia organyls, the purification of the end product and the unsatisfactory yields.

Another production possibility for tricyclohexylphosphine is the hydrogenation of triphenylphosphine. However, the usual hydrogenation catalysts are unsuitable for this purpose because they are complexed by the phosphorus atom and thus deactivated. Only a few niobium and tantalum catalysts are suitable (J. Chem. Soc. Chem. 1992, 8, 632, J. Chem. Soc, Chem. Commun. 1995, 8, 849, WO

93/321192). These are not only very expensive, but are also destroyed during the reaction.

It was therefore an object of the present invention to provide a method which overcomes the disadvantages described above. In particular, it should be industrially applicable, require no complicated process steps and emanate from inexpensive, readily available reactants.

The object is achieved by a process for the preparation of compounds of the formula I. wherein

R is a radical of the formula II

or is a linear or branched alkyl radical having 1 to 8 carbon atoms, the 1, 2, 3 or 4 radicals of the formula III

and also 1 to 4 substituents of F ,, ormel IV

can carry;

X and Y independently represent O or NR ⁸ ;

each R ¹ is independently _Ci-C4 -alkyl, _{Ci-C4-haloalkyl,} Ci-C ₄ hydroxyalkyl, C ₃ -C ₀ - represents cycloalkyl, C ₃ -Cio-halocycloalkyl, halogen, OR ² or COR ³ ;

R ^{2 is} H or C 1 -C ₄ alkyl;

R ^{3 is} H, C 1 -C ₄ alkyl, OR ⁴ or NR ⁵ R ⁶ ;

R ⁴ , R ⁵ and R ⁶ independently of one another are H or C 1 -C ₄ -alkyl; R ^{7 is} H, C 1 -C ₄ -alkyl or C ₂ -C ₄ -hydroxyalkyl; or in the event that two substituents of the formula IV are bonded to the same or to two adjacent carbon atoms of the alkyl radical, two radicals R ^{7 can} also together form a linear or branched alkylene group having 1 to 6 carbon atoms;

R ⁸ is H, dC ₄ alkyl or C ₂ -C ₄ hydroxyalkyl;

each x is independently 0, 1, 2 or 3;

a is 2, 3 or 4;

b is 0, 1, 2, 3k, 4, 5, 6, 7, 8, 9 or 10; and

# denotes the point of attachment to the rest of the molecule;

or hydrohalides thereof, comprising the following step:

Reaction of compounds of the formula V

wherein

R 'is a radical of the formula II or a linear or branched alkyl radical having 1 to 8 carbon atoms, the 1, 2, 3 or 4 radicals of the formula VI

and may also carry 1 to 4 substituents of the formula IV; Z is halogen; and

R ¹ , x and # are as defined above;

with hydrogen at a pressure of 10 to 300 bar.

This method will be referred to as method A below.

Formulas V and VI are not intended to be interpreted as limiting the actual electronic structure of the phosphine dihalide group. In particular, they should not be interpreted to mean that the halogen atoms are covalently bonded to the phosphorus atom, because it can also ionic bonds are present (eg in the form of [PX] ⁺ X ^"). They are to be understood as two cyclohexyl and the rest R 'or the alkyl radical covalently and two halogen atoms are bonded via an unspecified binding form (which may be covalent or ionic and the same or different for the two halogen atoms) to the phosphorus atom.

In the context of the present invention, the generic terms have the following meanings:

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine and in particular chlorine or bromine.

C 1 -C 4 -alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples of these are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

Ci-Cβ-alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Examples thereof are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neo-pentyl, 2,2-dimethylpropyl, hexyl, isohexyl and positional isomers thereof.

Ci-Cs-alkyl ("alkyl radical having 1 to 8 carbon atoms") represents a linear or branched alkyl radical having 1 to 8 carbon atoms. Examples include, in addition to the examples already mentioned in CrC ₄ -AlkVl heptyl, 3,3-dimethylpentyl, octyl and 2-ethylhexyl and position isomers thereof.

Ci-Cio-alkyl is a linear or branched alkyl radical having 1 to 10 carbon atoms. Examples of these are, in addition to the examples already mentioned for C 1 -C 6 -alkyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl and 2-propylheptyl, as well as positional isomers thereof. If the alkyl radical is substituted and carries, for example, 1, 2, 3 or 4 radicals of the formulas III, VI, VIII or XI, then it goes without saying that in the abovementioned alkyl radicals, the corresponding number of hydrogen atoms is replaced by these substituents is.

Ci-C4-hydroxyalkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced by a hydroxy group, wherein each carbon atom usually carries at most one hydroxy group. Examples of these are hydroxymethyl, 2-hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl and the like.

C 2 -C 4 -hydroxyalkyl is a linear or branched alkyl radical having 2 to 4 carbon atoms, in which one or more hydrogen atoms are replaced by a hydroxy group, each carbon atom usually carrying at most one hydroxyl group, and as a rule the Hydroxy group (s) is not attached to the carbon atom at the 1-position of the alkyl group. Examples of these are 2-hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl and the like.

Ci-Cβ-hydroxyalkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms, in which one or more hydrogen atoms are replaced by a hydroxy group, each carbon atom usually carries at most one hydroxy group. Examples of these are, in addition to the examples mentioned for C 1 -C 4 -hydroxyalkyl, pentaerythritol and sorbitol.

Ci-Cio-hydroxyalkyl is a linear or branched alkyl radical having 1 to 10 carbon atoms, in which one or more hydrogen atoms are replaced by a hydroxy group, each carbon atom usually carries at most one hydroxy group. Examples of these are hydroxymethyl, 2-hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, pentaerythritol, sorbitol and the like.

Ci-C4-haloalkyl represents a linear or branched alkyl radical having 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced by a halogen atom. Examples of these are chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, 2,2- and 1, 2-dichloroethyl, 1, 1, 2, 1, 2,2 and 2,2,2- Trichloroethyl, pentachloroethyl, fluoroethyl, 2,2- and 1, 2-difluoroethyl, 1, 1, 2-, 1, 2,2- and 2,2,2-trifluoroethyl, pentafluoroethyl, chloropropyl, dichloropropyl, trichloropropyl, pentachloropropyl , Heptachloropropyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, chlorobutyl, dichlorobutyl, trichlorobutyl, fluorobutyl, difluorobutyl, trifluorobutyl, and the like. C3-Cio-Cycloalkyl is an optionally substituted mono- or polycyclic cycloalkyl group having 3 to 10 carbon atoms as ring members. Examples of monocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Examples of polycyclic groups are nomenulyl, decalinyl, adamantyl and the like. Suitable substituents are, for example, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and halogen.

C3-Cio-Halocycloalkyl represents an optionally substituted mono- or polycyclic cycloalkyl group having 3 to 10 carbon atoms as ring members, in which one or more hydrogen atoms are replaced by a halogen atom. Examples thereof are chlorocyclopropyl, dichlorocyclopropyl, fluorocyclopropyl, difluorocyclopropyl, chlorocyclopentyl, dichlorocyclopentyl, fluorocyclopentyl, difluorocyclopentyl and the like.

Aryl in the context of the present invention is an aromatic hydrocarbon radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthracenyl or phenanthrenyl. The aryl radical may be unsubstituted or carry 1 to 4 substituents. Suitable substituents are, for example, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, halogen, nitro, CN, COOR ^d , COR ^e , SO ₂ OR ^f , SO ₂ Rs, SR ^h and NR'RJ, wherein R ^d , R ^e , R ^f , R a and R ^{h are} independently H or Ci-Cβ-alkyl and wherein R ¹ and RJ is H, Ci-Cβ-alkyl or C ² -C 6 -hydroxyalkyl. Examples of these are phenyl, naphthyl, chlorophenyl, methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, 1-butylphenyl, 2-butylphenyl, isobutylphenyl, tert-butylphenyl, nitrophenyl, carboxyphenyl, formylphenyl, acetylphenyl, sulfonylphenyl, methylsulfonylphenyl, sulfonylnaphthyl, methylsulfonylnaphthyl , Carboxynaphthyl and the like.

Aryl-C 1 -C 4 -alkyl is a C 1 -C 4 -alkyl radical which is substituted by an aryl group. Examples of these are benzyl and 1- and 2-phenylethyl.

Alkylene is a difunctional aliphatic saturated linear or branched radical having, for example, 1 to 8 or 1 to 6 carbon atoms. Examples of these are methylene (-CH ₂ -), 1, 1-ethylene (-CH (CH ₃ ) -), 1, 2-ethylene (-CH ₂ CH ₂ -), 1, 1-propylene (-CH (CH ₂ CH ₃ ) -), 2,2-propylene (-C (CH ₂ ) ₂ -), 1, 2-propylene (-CH ₂ -CH (CH ₃ ) -), 1, 3-propylene (-CH ₂ CH ₂ CH ₂ -), 1, 1-butylene (-CH (CH ₂ CH ₂ CH ₃ ) -), 2,2-butylene (-C (CH ₃ ) (CH ₂ CH ₃ ) -), 1, 2 Butylene (-CH ₂ -CH (CH ₂ CH ₃ ) -), 2,3-butylene (-CH (CH ₃ ) -CH (CH ₃ ) -), 1, 4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), 1, 3-pentylene (CH (CH ₃ ) -CH ₂ -CH (CH ₃ ) -), 2,2-dimethyl-1,3-propylene (-CH ₂ -C (CH ₂ ) ₂ -CH ₂ -), 1, 5-pentylene (- (CH ₂ ) ₅ -) and the like.

The statements made below on preferred embodiments of the process according to the invention, the reactants used and the products obtained apply both alone and preferably in combination with one another. In process A, the reduction of compound V with hydrogen is preferably carried out without the use of a transition metal catalyst. In particular, the reduction takes place without the use of catalysts.

Z is preferably Cl, i. the starting material V to be reduced is preferably a phosphine dichloride.

In process A, the pressure is preferably at least 30 bar, e.g. 30 to 300 bar, preferably 30 to 250 bar, particularly preferably 30 to 200 bar and in particular 30 to 150 bar; more preferably at least 50 bar, e.g. 50 to 300 bar, preferably 50 to 250 bar, particularly preferably 50 to 200 bar and in particular 50 to 150 bar; more preferably at least 80 bar, e.g. 80 to 300 bar, preferably 80 to 250 bar, particularly preferably 80 to 200 bar and in particular 80 to 150 bar; and in particular at least 90 bar, e.g. 90 to 300 bar, preferably 90 to 250 bar, more preferably 90 to 200 bar and in particular 90 to 150 bar.

The pressure may also be provided either by hydrogen alone or by a mixture of hydrogen with an inert gas, such as nitrogen, argon or carbon dioxide, and / or in the event that the reduction is carried out in the presence of ammonia (see below for details on this embodiment) be built up with ammonia. If a mixture of hydrogen and inert gas and / or ammonia is used, the partial pressure of hydrogen must of course be so high that the reduction of compound V can succeed. The partial pressure of hydrogen in the mixture is preferably at least 50%, particularly preferably at least 70% and in particular at least 80% of the total pressure. Preferably, the pressure is built up solely by hydrogen.

Hydrogen may be in the form of hydrogen-containing gas mixtures, e.g. in the form of a technical gas, i. with a certain proportion of foreign gases, e.g. with up to 5% by volume of foreign gases, or in pure form, i. in a purity of at least 98% by volume, preferably of at least 99% by volume and in particular of at least 99.5% by volume of hydrogen, based on the total volume. Examples of hydrogen-containing gas mixtures are those from the reforming process. Preferably, hydrogen is used in pure form.

Hydrogen is used in equimolar amounts or preferably in molar excess, based on the compound V to be reduced. The molar ratio of hydrogen used to compound V used is preferably 1: 1 to 100: 1, particularly preferably 1: 1 to 20: 1 and in particular 1: 5: 1 to 10: 1.

The pressures given above refer to the pressure prevailing at the beginning of the reaction. This can be especially true when carrying out the method A in batch mode in the course of the reaction decrease, for example, as the hydrogen is consumed. If the pressure drop is at most 20%, preferably at most 10% and especially at most 5% of the initial pressure, the pressure need not be set again to the value of the initial pressure. Of course, however, it can be brought to the value of the initial pressure or even to an even higher pressure, for example by repressing hydrogen and / or inert gas and / or ammonia, preferably hydrogen, optionally in admixture with inert gas.

The pressures given above refer to the value of the pressure at the prevailing reaction temperature.

The reaction is preferably carried out at a temperature from 0 to 250 ⁰ C, particularly preferably from 20 to 200 ⁰ C, more preferably from 50 to 200 ⁰ C, even more preferably from 80 to 200 ⁰ C and in particular from 100 to 200 ⁰ C, eg from 120 to 180 ^° C. or from 140 to 180 ^° C.

The reaction can be carried out either in bulk or in a suitable solvent. Preferably, the reaction is carried out in a suitable solvent. Suitable solvents are those which are inert under the given reaction conditions, i. react neither with the reactants nor with the reaction product and are not hydrogenated especially under the reaction conditions themselves. Examples of suitable solvents are alkanes such as pentane, hexane, heptane and the like, cycloalkanes such as cyclopentane, cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene and the xylenes, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the dichlorobenzenes, high boiling ethers such as diethylene glycol, triethylene glycol and higher polyethers, and nitriles such as acetonitrile, propionitrile and benzonitrile. Preferred solvents are the abovementioned aromatic hydrocarbons, in particular toluene.

In a preferred embodiment of process A according to the invention, the reduction, ie the reaction of compound V with hydrogen, is carried out in the presence of a base. Suitable bases are, for example, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, N-containing basic heterocycles, such as piperidine, piperazine, morpholine, pyridine, picoline and lutidine, ammonia and amines. Preferred bases are those which are at least partially soluble in the reaction medium of the reduction reaction. When using the solvents mentioned above, these are mainly N-containing basic heterocycles, ammonia and amines. Particularly preferred bases are ammonia and amines, especially those of the formula NR ^a R ^b R ^c , wherein R ^a , R ^b and R ^c independently of one another are H, ^C 1 -C 10 -alkyl, C 1 -C 10 -hydroxyalkyl, C 3 -C 10 -alkyl, -Cycloalkyl, aryl or aryl-Ci-C4-alkyl, wherein at least one of the radicals R ^a , R ^b or R ^c does not stand for H. Examples of such amines are methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, diisopropylethylamine, butylamine, dibutylamine, tributylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, aniline, benzylamine and the like. In particular, ammonia is used.

The molar ratio of the base used to the compound V used is preferably 1: 1 to 10: 1, more preferably 1: 1 to 3: 1 and in particular 1: 1 to 2: 1.

Alternatively, the reduction does not occur in the presence of a base.

In an alternatively preferred embodiment of process A according to the invention, the reduction is carried out in the presence of a Lewis acid. Preferred Lewis acids are the chlorides of (half) metals with an electron gap, such as boron trichloride, aluminum trichloride, silicon tetrachloride, stannic chloride, titanium (IV) chloride, vanadium (V) chloride, iron (III) chloride and zinc chloride Zinc, tin (IV), iron (III) - and in particular aluminum chloride are particularly preferred.

The molar ratio of Lewis acid used to compound V used, based on each PZ2 group, is preferably 4: 1 to 1:10, more preferably 2: 1 to 1: 2.

The reaction time depends, inter alia, on the batch size, the reaction pressure and the reaction temperature and can in individual cases by the skilled person, e.g. be determined by simple preliminary tests.

The reaction can be designed both as a batch mode of operation as well as semicontinuously or continuously.

Suitable reactors are all reaction vessels known to the person skilled in the art for pressure reactions, such as autoclaves, pressure reactors and tubular pressure reactors.

The batch procedure is usually carried out by initially introducing the compound V in a solvent and optionally in admixture with a base in a suitable reaction vessel, which is preferably rendered inert before or after, for example by multiple injection of hydrogen and or inert gas, such as nitrogen, argon or carbon dioxide, and relax. Subsequently, hydrogen is optionally injected in a mixture with an inert gas and / or ammonia to the desired initial pressure. The reaction temperature is preferably adjusted before the hydrogen is pressurized. If the pressure decreases too much, hydrogen and / or inert gas and / or ammonia again, preferably Hydrogen and optionally inert gas and in particular only hydrogen introduced to the desired pressure. After completion of the reaction, the vessel is expanded and the reaction product worked up as described below.

In the continuous procedure, the reactants are passed in, if appropriate

Inert gas, optionally a solvent and optionally a base through a suitable pressure reactor, which is adjusted to the desired pressure and the desired temperature. If desired, the discharge can be recirculated several times.

In the reduction reaction, the hydrohalide of the compound I is usually formed in a reaction procedure without a base. The halide ion originates from the compound V used as the starting material; i.e. when using compounds V, in which Z is chlorine, as starting material is obtained in a reaction procedure without base, the corresponding compound I usually first in the form of its hydrochloride. This can then be isolated and purified according to conventional methods. For example, it is possible to remove the solvent which may be present, for example by distillation, suitably under reduced pressure. As solvents are generally used as solvents in which the hydrohalide formed is not or only slightly soluble, separation by filtration or decantation is also possible and regularly preferred for ease of technical feasibility. The residual solid can then be purified according to conventional methods, for example by washing, trituration or recrystallization. Prior to removal of the solvent, the reaction mixture may also first be treated with another solvent in which the hydrohalide is still more insoluble, usually an even more nonpolar solvent, to facilitate separation via filtration or decantation.

The preparation of the free phosphine from the hydrohalide is carried out by conventional methods for the liberation of free bases from their acid addition salts, for example thermally, optionally in combination with stripping the liberated hydrohalic acid. The stripping is carried out, for example, by introducing an inert gas, such as nitrogen, carbon dioxide or argon, in a sufficiently strong gas stream. Alternatively, the release is carried out by reacting the hydrohalide with a base. Suitable bases are those mentioned above. Preferably, inorganic bases are used, alkali metal hydroxides such as sodium or potassium hydroxide being preferred. The reaction is generally carried out in a polar solvent in which the hydrohalide is soluble, but the free base is not or only poorly, for example water, C 1 -C 3 -alcohols, such as methanol, ethanol, propanol or isopropanol, or mixtures thereof , The resulting free base is then isolated by conventional methods, for example by filtration, sedimentation, centrifugation or extraction with a nonpolar solvent. It is also possible to convert the initially formed hydrohalide directly, ie without prior purification, into the free base and then subjecting it to suitable purification steps; however, the first variant is preferred.

In a reaction in the presence of a base arises, especially when the base is used in excess or at least equimolar, directly the free phosphine I. This is after removal of any solvent present, excess base and the reaction products of the base with the formed in the hydrogenation Halogenic acid, if desired, purified by conventional methods. Thus, the compound 1, which is usually dissolved in the solvent, are separated from solid constituents, for example from the formed reaction products of the base with the halogen acid (eg ammonium salts), for example by filtration or decantation, freed from the solvent, for example by distillation , suitably under reduced pressure, and then, if desired, further purified, for example by means of extractive, distillative or chromatographic methods.

Due to the oxidation sensitivity of phosphines I and their acid addition salts, the reaction of the reactants and the isolation and purification of the products is preferably carried out under exclusion of oxygen; e.g. It is preferable to use inertized equipment and possibly degassed solvents and avoid contact with air.

The compound V used as starting material in process A according to the invention is preferably prepared by reacting a corresponding compound VII

wherein

R "is a radical of the formula II or a linear or branched alkyl radical having 1 to 8 carbon atoms which is 1, 2, 3 or 4 radicals of the formula VIII

and may also carry 1 to 4 substituents of the formula IV; and

R ¹ , x and # are as defined above;

available with a halogenating agent.

Suitable compounds are all customary halogenating agents, such as phosgene, the tri- and pentahaloides of phosphorus, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorodibromide trifluoride, the pentahalides of antimony and arsenic, such as antimony pentachloride, antimony pentabromide, arsenic pentafluoride, arsenic pentachloride and arsenic pentabromide, thionyl chloride, Oxalyl chloride, sulfur tetrafluoride and the like, with phosgene, phosphorus trichloride, thionyl chloride and oxalyl chloride, and especially phosgene, phosphorus trichloride and thionyl chloride, being preferred. Specially used phosgene.

The halogenation can be carried out in analogy to known processes for the conversion of phosphine oxides into the corresponding phosphine dihalides, as described, for example, in US Pat. Nos. 4,727,193, DE 1192205, DE 1259883, DE 19532310, Z. Anorg. AIIg. Chem. 369, 1969, 33, Chem. Ber. 92, 1959, 2088 and Houben-Weyl, Methoden der Organischen Chemie, Vol. 12/1, 1963, 129.

The reaction is preferably carried out in a suitable solvent. Suitable solvents are those which are inert under the given reaction conditions, ie react neither with the reactants nor with the reaction product and which in particular are not halogenated under the reaction conditions themselves. Examples of suitable solvents are alkanes such as pentane, hexane, heptane and the like, cycloalkanes such as cyclopentane, cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene and the xylenes, and halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the dichlorobenzenes. If one wishes to use the phosphinedihalogenide V obtained in the halogenation reaction without work-up or isolation in the subsequent reduction reaction, the solvent is desirably chosen, of course, so that it is also suitable for the subsequent reduction step. Preferred solvents are the abovementioned aromatic hydrocarbons, in particular toluene. Since the halogenation reaction is generally exothermic, the reaction is preferably carried out under cooling or at least so that evaporating solvent can not escape and is condensed back into the reaction vessel. In addition, the halogenating agent is preferably added not at one time but continuously or in portions so that the exothermicity of the reaction can be controlled.

The halogenating agent is used in relation to the compound VII at least equimolar, and preferably in molar excess, these molar details refer to the halide contained in the halogenating agent capable of halogenation. Preferably, the molar ratio of reactive halogen atoms present in the halogenating agent (ie halogenating halogen atoms capable of halogenation) to the phosphine oxide VII is 1: 1 to 100: 1, more preferably 1: 1 to 50: 1, more preferably 1: 1 to 20 : 1, even more preferably 1: 1 to 10: 1 and especially 1: 1 to 5: 1, eg 1: 1 to 3: 1 or to 2: 1.

After completion of the reaction, the reaction mixture is freed by conventional methods of excess halogenating agent, for example by stripping with an inert gas. The reaction product can then be isolated according to customary processes and, if desired, also purified. In general, however, the purity is sufficient and the product can be used without further purification steps in the next step. If the solvent chosen was one which can also be used in the subsequent reduction step (reduction to compound I or its hydrohalide), then the phosphine dihalide V need not be isolated, but may be in the form of the entire, but preferably freed from, halogenating agent reaction solution be used in the following step.

Due to the sensitivity to hydrolysis of the compound V, it goes without saying that the halogenation reaction as well as the subsequent subsequent work-up and purification steps and the further reaction (reduction) should take place under substantially anhydrous conditions, for example by using dry and optionally inertized reaction vessels and water - free solvent and reactants.

The compound VII used in the halogenation reaction is available, for example, according to step (a) of method B described below or method C described below. A further subject of the present invention is a process for the preparation of compounds I or hydrohalides thereof, comprising the following steps:

(a) hydrogenation of compounds of formula IX

wherein

R '"for a radical of the formula X.

or is a linear or branched alkyl radical having 1 to 8 carbon atoms, the 1, 2, 3 or 4 radicals of the formula XI

and may also carry 1 to 4 substituents of formula IV as defined above;

to compounds of formula VII as defined above;

(b) reacting the compounds of the formula VII obtained in step (a) with a halogenating agent to give compounds of the formula V as defined above;

(c) reacting the compounds of formula V obtained in step (b) with a reducing agent to give compounds I or a hydrohalide thereof. This method will be referred to as method B below.

The hydrogenation step (a) of the process B according to the invention can be carried out according to customary processes of the prior art for the reduction of aromatics to the corresponding cycloalkanes and more particularly of aryl, especially phenyl-substituted, phosphine oxides to the corresponding cycloalkyl-substituted phosphine oxides.

The hydrogenation is generally carried out in the presence of a suitable hydrogenation catalyst. As hydrogenation catalysts, it is possible to use generally all prior art catalysts which catalyze the hydrogenation of aromatics to the corresponding cycloalkanes and, more particularly, aryl and especially phenyl-substituted phosphine oxides to the corresponding cycloalkyl-substituted phosphine oxides. The catalysts can be used both in heterogeneous phase as well as homo gene catalysts. Preferably, the hydrogenation catalysts contain at least one Group VIII metal.

Particularly suitable metals of group VIII are selected from ruthenium, cobalt, rhodium, nickel, palladium and platinum and in particular from ruthenium, rhodium, nickel and platinum. The hydrogenation catalysts particularly preferably contain ruthenium as the active metal.

The metals can also be used as mixtures. In addition, the catalysts in addition to the metals of Group VIII also small amounts of other metals, such as Group VIIb metals, in particular rhenium, or metals of Group Ib, d. H. Copper, silver or gold, included.

If a heterogeneous catalyst is used, this is suitably present in finely divided form. The finely divided shape is achieved, for example, as follows:

a) Black catalyst: The metal is deposited reductively shortly before use as a catalyst from the solution of one of its salts.

b) Adams catalyst: The metal oxides, in particular the oxides of platinum, palladium and also ruthenium, are reduced in situ by the hydrogen used for the hydrogenation.

c) Skeleton or Raney Catalyst: The catalyst is prepared as a "metal sponge" from a binary alloy of the metal (especially nickel or cobalt) with aluminum or silicon by dissolving a partner with acid or alkali. Residues of the original alloying partner often act synergistically. d) Supported catalyst: Black catalysts can also be precipitated on the surface of a carrier substance. Suitable carriers and carrier materials are described below.

Such heterogeneous catalysts are described in general form, for example, in the Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin, 1988, p. 288. In addition, heterogeneous hydrogenation catalysts which are suitable for the reduction of aromatics to cycloalkanes are described in more detail in the following documents:

US 3,597,489, US 2,898,387 and GB 799,396 describe the hydrogenation of benzene to cyclohexane over nickel and platinum catalysts in the gas or liquid phase. GB 1 155 559 describes the use of a rhenium doped nickel catalyst for the hydrogenation of benzene. US 3,202,723 describes the hydrogenation of benzene with Raney nickel. Ruthenium-containing suspension catalysts doped with palladium, platinum or rhodium are used in SU 319582 for the hydrogenation of benzene to cyclohexane. Alumina-supported catalysts are described in US 3,917,540 and US 3,244,644. The hydrogenation catalysts described in these references are incorporated herein by reference.

The following documents specifically describe the reaction of phenyl-substituted phosphine oxides into cyclohexyl-substituted phosphine oxides: The use of rhodium (III) / platinum (IV) mixed oxides is described, inter alia, in Catalysis Letters, 1991, 8 (1), 23-26 and described in DD 283633. In Chem. Lett. 1986, 12, 2061-2064 and in Chem. Soc, Chem. Commun. 1984, 24, 1641-1643, alumina-supported rhodium catalysts are used. The use of platinum as a hydrogenation catalyst is described, for example, in Zh. Obshch. Khim. 41 (103), 1971, 1944-1950, in Zh. Obshch. Khim. 38, 1968, 10, 2346-2347 and in Izv. Akad. SSSR 1967, 4, 949-950. In Zh. Obshch. Khim. 55 (17), 1985, 2667-2674, in Chem. Pharm. Bull. 40 (11), 1992, 2921-2926 and in Angew. Chem. Int. Ed. 40 (7), 2001, 1235-1238 Raney nickel is used as a hydrogenation catalyst. The use of carbon supported ruthenium is described in Chem. Lett. 1984, 9, 1603-1606

Depending on the configuration of the hydrogenation process, the carrier material may have different shapes. If the hydrogenation is carried out, for example, with a mobile catalyst phase, for example in a slurry reactor, for example in a stirred tank, moving bed, fluidized bed, fluidized bed or bubble column reactor, the support material is generally used in the form of a finely divided powder. On the other hand, if the hydrogenation is carried out with immobile catalyst phase and the catalyst is used in the form of a fixed-bed catalyst, for example in a bottoms or trickle reactor, moldings are used rather as support materials. Such shaped bodies can be in the form of spheres, tablets, cylinders, hollow cylinders, Raschig rings, strands, saddles, stars, spirals, etc. are present in a size (dimension of the longest extent) of about 1 to 30 mm. In addition, the carriers can be present in the form of monoliths, as described, for example, in DE-A-19642770. Furthermore, the carriers can be used in the form of wires, sheets, grids, nets, fabrics and the like.

The carriers can be made of metallic or non-metallic, porous or nonporous material.

Suitable metallic materials are, for example, high-alloy stainless steels. Suitable non-metallic materials are, for example, mineral materials, e.g. natural and synthetic minerals, glasses or ceramics, plastics, e.g. artificial or natural polymers, or a combination of both.

Preferred support materials are carbon, in particular activated carbon, silicon carbide, (semi-) metal oxides, such as silica, in particular amorphous silica, alumina, magnesia, titania, zirconia and zinc oxide, and also the sulfates and carbonates of alkaline earth metals, such as calcium carbonate, calcium sulfate, magnesium carbonate, Magnesium sulfate, barium carbonate and barium sulfate.

The catalyst may be applied to the support by conventional methods, e.g. by soaking, wetting or spraying the carrier with a solution containing the catalyst or a suitable precursor thereof.

Suitable carriers and methods for applying the catalyst to these are described, for example, in DE-A-10128242, to which reference is hereby fully made.

Homogeneous hydrogenation catalysts can also be used in process B according to the invention. Examples of these are the nickel catalysts described in EP-A-0668257. However, a disadvantage of using homogeneous catalysts is their production costs and also the fact that they are generally not regenerable.

Therefore, heterogeneous hydrogenation catalysts are preferably used in the process according to the invention.

Examples of supported catalysts are palladium, nickel or ruthenium on carbon, in particular activated carbon, silica, in particular amorphous silica, silicon carbide, barium carbonate, calcium carbonate, magnesium carbonate or aluminum oxide, wherein the supports may be in the forms described above. loading preferred carrier form are the moldings described above. A particularly preferred carrier is alumina.

The metallic catalysts can also be used in the form of their oxides, in particular penta-dium oxide, platinum oxide, rhodium oxide, ruthenium oxide or nickel oxide, which are then reduced under the hydrogenation conditions to the corresponding metals. These can also be used in supported form. Preferred supports are also selected here from coal, in particular activated carbon, silicon dioxide, in particular amorphous silicon dioxide, silicon carbide, barium carbonate, calcium carbonate, magnesium carbonate and in particular aluminum oxide, wherein the supports can be present in the forms described above. Preferred carrier form are the moldings described above.

An example of a metal sponge is Raney Nickel.

In step (a) of process B according to the invention, particular preference is given to using a ruthenium-containing hydrogenation catalyst which preferably contains metallic ruthenium, which is optionally supported, or in particular ruthenium (IV) oxide, which may also be supported. With regard to suitable and preferred ruthenium catalysts and embodiments of the hydrogenation step (a) when using ruthenium catalysts, reference is made to the comments on method C according to the invention.

The amount of catalyst to be used depends, inter alia, on the respective catalytically active metal and on its form of use and can be determined by the person skilled in the individual case. In general, the hydrogenation catalyst may be used in an amount of 0.01 to 70% by weight, preferably 0.05 to 20% by weight and more preferably 0.1 to 10% by weight, based on the weight of the compound IX to be hydrogenated , are used. The stated amount of catalyst refers to the amount of active metal, d. H. on the catalytically active component of the catalyst. Precious metal catalysts are regularly used in a smaller amount by a factor of 10 than non-noble metal catalysts.

The hydrogenation is carried out at a temperature of preferably 0 to 250 ⁰ C, particularly preferably from 20 to 200 ⁰ C, more preferably from 50 to 200 ° C and especially from 100 to 180 ⁰ C.

The reaction pressure of the hydrogenation reaction is preferably in the range of 1 to 300 bar, more preferably 10 to 300 bar, more preferably 50 to 300 bar, and most preferably 100 to 300 bar. The pressure can be built up either by hydrogen alone or by a mixture of hydrogen with an inert gas such as nitrogen, argon or carbon dioxide. If a mixture of hydrogen and inert gas is used, the partial pressure of hydrogen must of course be so high that the hydrogenation of the phosphine oxide IX can succeed. Preferably, the partial pressure of hydrogen in the mixture is at least 50%, more preferably at least 70% and in particular at least 80% of the total pressure. Preferably, the pressure is built up solely by hydrogen.

The reaction pressure as well as the reaction temperature depend, inter alia, on the activity and amount of the hydrogenation catalyst used and in individual cases can be determined by a person skilled in the art.

Hydrogen is used in molar excess, based on the compound IX to be reduced. The molar ratio of hydrogen used to compound IX used is preferably 500: 1 to 10: 1, particularly preferably 100: 1 to 10: 1 and in particular 50: 1 to 10: 1.

The pressures given above refer to the pressure prevailing at the beginning of the reaction. This may decrease, especially when carrying out step (a) of process B in batch mode during the course of the reaction, e.g. to the extent that hydrogen is consumed. If the pressure drop is at most 20%, preferably at most 10% and especially at most 5% of the initial pressure, the pressure need not be set again to the value of the initial pressure. Of course, however, it can be brought to the value of the initial pressure or even to an even higher pressure, e.g. by repressing hydrogen and / or inert gas, preferably hydrogen, optionally mixed with inert gas.

The hydrogenation is preferably carried out in a suitable solvent. Suitable solvents are those which are inert under the reaction conditions, ie react neither with the starting material or product nor be changed themselves. Especially For example, suitable solvents are not self-hydrogenated under the hydrogenation conditions. Preferably, the solvents are saturated, ie they contain no CC double bonds. Suitable solvents include alkanes, in particular Cs-Cio-alkanes, such as pentane, hexane, heptane, octane, nonane, decane and isomers thereof, cycloalkanes, in particular Cs-Cs-cycloalkanes, such as cyclopentane, cyclohexane, cycloheptane or cyclooctane, open-chain and cyclic ethers, such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, ketones, such as acetone or ethyl methyl ketone, alcohols, in particular C 1 -C 3 -alkanols, such as methanol, ethanol, n-propanol or isopropanol, and also carboxylic acids, such as acetic acid and propionic acid. Also suitable are mixtures of the abovementioned solvents and mixtures thereof with water. Preference is given to polar solvents, such as the abovementioned cyclic ethers, in particular tetrahydrofuran or 1,4-dioxane, the abovementioned ketones, alcohols, carboxylic acids, mixtures thereof or mixtures with water. In particular, aqueous or non-aqueous acetone, ethanol or methanol are used in pure form or in a mixture with water or acetic acid, acetic acid in the form of glacial acetic acid or in the form of aqueous acetic acid or especially tetrahydrofuran.

The hydrogenation step (a) can be configured both continuously and discontinuously.

The hydrogenation in the batch mode is usually carried out by initially introducing the compound IX and the catalyst in the solvent and then starting the hydrogen. Depending on the hydrogenation catalyst used, the hydrogenation is carried out at elevated temperature and / or at elevated pressure. Work up is generally as described below. If no overpressure is used, the usual state-of-the-art reaction devices are suitable for batch processes suitable for atmospheric pressure. Examples of these are suspension reactors for discontinuous operation, e.g. conventional stirred tank, which are preferably equipped with a Siedekühlung, suitable mixers, introduction devices, optionally heat exchanger elements and / or inerting devices. In general, however, must be worked under increased pressure.

If the hydrogenation step (a) is designed as a continuous process, the exact procedure depends on the type of catalyst used and in particular on whether it is mobile (eg as suspended particles) or stationary (ie as a fixed bed catalyst) in the reactor. Suitable reactors for the use of mobile catalyst phases are continuous slurry reactors, such as continuous stirred tanks, moving bed reactors, fluidized bed reactors, fluidized bed reactors and bubble column reactors. Suitable fixed bed reactors are, for example, bottom and trickle reactors. The reaction is usually carried out according to the usual procedure for the respective reactors for three-phase reactions.

For the reaction under pressure, the usual, known from the prior art pressure vessels, such as autoclaves, stirred autoclave and pressure reactors can be used.

The hydrogenation is preferably carried out in a slurry reactor or in a fixed bed reactor, preferably under elevated pressure.

After completion of the hydrogenation, the catalyst and the solvent are usually removed. The heterogeneous catalyst is preferably separated by filtration or by sedimentation and removal of the upper, product-containing phase. Other separation methods for removing solids from solutions, such as centrifuging, are also suitable for removing the heterogeneous catalyst. The removal of homogeneous catalysts is carried out by conventional methods for the separation of in-phase mixtures, for example by chromatographic methods. Optionally, depending on the type of catalyst, it may be necessary to deactivate it prior to removal. This can be done by conventional methods, for example by washing the reaction solution with protic solvents, e.g. with water or with C 1 -C 3 -alkanols, such as methanol, ethanol, propanol or isopropanol, which are, if necessary, basic or acidic.

The removal of the solvent is carried out by conventional methods, for example by distillation, in particular under reduced pressure.

The product obtained can, if desired, be purified by conventional methods, e.g. B. by distillation.

With regard to suitable and preferred embodiments of the halogenation step (b), reference is made to the statements made above on method A for the preparation of the compound V used there as starting material.

The reduction step (c) of the process B according to the invention can be carried out in analogy to prior art processes for the reduction of phosphine dihalides substituted by three hydrocarbon radicals, in particular triphenylphosphine dihalides, to the correspondingly substituted phosphines, especially triphenylphosphine.

As the reducing agent, there may be mentioned base metals such as the metals of the first to fifth main groups and the subgroup elements which are not noble metals, especially those of the groups INb (Sc, Y, La), IVb (Ti, Zr, Hf), Vb (V , Nb, Ta), VIb (Cr, Mo, W), VIIb (Mn, Tc, Re), VIII (Fe, Co, Ni) and IIb (Zn), further semimetals such as boron, silicon, arsenic, selenium and tellurium, complex metal hydrides, such as lithium aluminum hydride, elemental phosphorus, elemental carbon or hydrogen.

It goes without saying that the choice of the reducing agent also depends on the nature of the radical R ¹ , which should remain unchanged under the reduction conditions. Thus, for example, no lithium aluminum hydride is used as the reducing agent when R ^{1 is} an ester radical (R ¹ = COR ³ ; R ³ = OR ⁴ ). The person skilled in the art knows which reducing agents are critical for which radicals R ¹ .

The use of hydrogen as a reducing agent is described separately; The following statements relate exclusively to the use of the metals, semimetals, of phosphorus or carbon as the reducing agent.

Preferred metals are those of the first main group, especially lithium, sodium or potassium, with sodium being particularly preferred, the second main group, especially magnesium, and the third main group, especially aluminum, and iron as a subgroup element. Among these, particularly preferred are sodium and aluminum.

Preferred semi-metal is silicon. This may be in elemental form or as an alloy, e.g. as ferrosilicon used.

Phosphorus can be used in both white and red modification.

The reduction of the compounds V to corresponding compounds I using base metals, semimetals, complex metal hydrides, elemental phosphorus or elemental carbon can be carried out, for example, analogously to the processes described in the following documents: DE-A-1259883 (reduction in the presence of zinc , Manganese, magnesium or, in particular, aluminum), DE-A-2638720 (reduction with sodium), US Pat. No. 3,780,111 (reduction with iron), DE-A-19532310 (reduction in the presence of non-noble metals or semimetals, especially of iron , Silicon, magnesium or in particular aluminum), Chem. Ber. 92, 2088 (1959) (reduction with sodium), Chem. Ber. 91, 1583 (1958) (reduction with lithium aluminum hydride), Z. Anorg. AIIg. Chem., Vol. 369, 1969, 33 (reduction with phosphorus), DE-A-4142679 (reduction with elemental silicon or silicon alloys) and US 4,727,193 (reduction with elemental carbon).

It goes without saying that the choice of a suitable reducing agent also depends on the radical R ¹ , which should not be changed under the reaction conditions in the rule. Thus, for example, in the event that R ^{1 is} an ester radical is (R ¹ = COR ³ , R ³ = OR ⁴ ), do not choose lithium aluminum hydride as the reducing agent, since this is known to be a good reducing agent for ester groups. The choice of suitable reducing agents as a function of the respective radical R ¹ can be made by a person skilled in the art with the aid of current literature.

The reduction is generally carried out in a suitable, usually high-boiling, aprotic and relatively polar solvent or, especially when the reactants are in the liquid phase at the desired reaction temperature, also in bulk. Suitable solvents are inert under the given reaction conditions, i. they do not react with either the reactants or the products, and in particular they are not self-reducing. The choice of a suitable solvent depends not only on the desired reaction temperature, but also on the reducing agent used. In the case of the use of base metals, semimetals or silicon as the reducing agent, suitable solvents are, for example, aromatic hydrocarbons such as benzene, toluene or xylenes, halogenated hydrocarbons, especially halogenated aromatic hydrocarbons such as chlorobenzene or the dichlorobenzenes, nitriles, especially aromatic nitriles, such as Benzonitrile, and also high-boiling ethers, such as diethylene glycol, triethylene glycol and higher polyethers. When elemental carbon is used, for example, hydrocarbons, including technical hydrocarbon mixtures, and especially alkanes, are suitable solvents.

The reaction temperature is usually relatively high and is for example 100 to 300 ° C, preferably 100 to 200 ° C.

The reaction pressure is usually of minor importance; It is possible to operate both at reduced pressure and at atmospheric pressure or overpressure of, for example, up to 10 bar, whereby a reaction regime at ambient pressure is appropriate.

The reducing agents are usually used in a finely divided form as possible to allow the shortest possible reaction time, for example in the form of powders, chips, wools, sponges or suspensions.

The reaction time depends on the application size, the reduction potential of the reducing agent used, the reaction temperature and other factors, and must be determined by the person skilled in the individual case, which can be done, for example, on the basis of simple preliminary tests.

The work-up after completion of the reaction is carried out in the usual manner. Thus, the excess reducing agent, which as a rule is in a heterogeneous phase, is separated off by customary processes, such as filtration, decantation or centrifuging, and the compound I is removed from the solvent and any other reaction product which may be present. removed the reducing agent (ie reducing agent in its oxidized form), which can be done for example by distillation or extraction.

If desired, the reaction product obtained may then be subjected to further purification steps, such as recrystallization, in particular by precipitation in the form of a hydrogen halide addition salt of phosphine I, extraction or column chromatography.

Due to the sensitivity to oxidation of the phosphine I formed, it goes without saying that all reaction, work-up and purification steps must be carried out under oxygen exclusion.

However, the reduction in step (c) of process B according to the invention is preferably carried out using hydrogen as the reducing agent. With regard to suitable and preferred process measures in the use of hydrogen as a reducing agent, reference is made to the comments on method A.

Finally, the invention provides a process for the preparation of compounds of the formula VII as defined above, comprising the following step:

Reaction of compounds of formula IX as defined above with hydrogen in the presence of a ruthenium-based hydrogenation catalyst.

This method will be referred to as method C below.

The ruthenium-based hydrogenation catalyst may be both a heterogeneous and a homogeneous catalyst. Preferably, it is selected from catalysts based on ruthenium (IV) oxide, its hydrate, ruthenium (VIII) oxide, its hydrate, elemental ruthenium, elemental ruthenium mixed with at least one metal of group VIIb, VIII or Ib, coordination compounds of ruthenium Ligands such as carbonyl, triphenylphosphine and halides, or ruthenium salts such as ruthenium chloride or ruthenium nitrate. The hydrogenation catalyst is preferably a heterogeneous catalyst and is thus preferably based on ruthenium (IV) oxide, its hydrate, ruthenium (VIII) oxide, its hydrate, elemental ruthenium or elemental ruthenium mixed with at least one metal of group VIIb, VIII or Ib. The catalyst is particularly preferably based on ruthenium (IV) oxide, its hydrate, elemental ruthenium or elemental ruthenium mixed with at least one metal of group VIIb, VIII or Ib and in particular ruthenium (IV) oxide or its hydrate.

In one embodiment, the ruthenium catalyst is preferably supported. Preferably, elemental ruthenium or ruthenium (IV) oxide (or its Hydrate) on a suitable carrier. Suitable carriers are listed above in the description of step (a) of method B; they may be made of metallic or non-metallic, porous or nonporous material. Preferred supports are selected from coal, in particular activated carbon, silicon carbide, (semi-) metal oxides, such as silica, in particular amorphous silica, alumina, magnesia, titania, zirconia and zinc oxide, and also the sulphates and carbonates of alkaline earth metals, such as calcium carbonate, calcium sulphate, Magnesium carbonate, magnesium sulfate, barium carbonate and barium sulfate. A particularly preferred carrier is alumina. Accordingly, a particularly preferred hydrogenation catalyst supported on alumina is ruthenium (V) oxide (hydrate).

A particularly suitable ruthenium hydrogenation catalyst is described in DE-A-2132547, which is hereby incorporated by reference. It is a ruthenium oxide hydrate, which is obtained by reacting a ruthenium salt, preferably the trihydrate of ruthenium (III) chloride, RuCl3-3H2θ, in aqueous solution with a base, preferably an alkali metal hydroxide, the ruthenium oxide Hydrate precipitated. The catalyst preferably has a particle size of about 40-60 Å, a relatively low ruthenium content of about 40-60% by weight, based on the total weight of the catalyst, and / or a water content of about 10-20% by weight on the total weight of the catalyst. When the catalyst is to be used supported, the reaction described above is suitably carried out in the presence of the support material to which it precipitates when it is formed. Alternatively, the precipitated ruthenium oxide hydrate may first be isolated, for example by filtration, sedimentation or centrifugation, and only then incorporated into the support material. Suitable carrier materials are the aforementioned.

Depending on the embodiment of the hydrogenation process C, the carrier material may have different shapes. If the hydrogenation is carried out, for example, with a mobile catalyst phase, for example in a slurry reactor, for example in a stirred tank, moving bed, fluidized bed, fluidized bed or bubble column reactor, the support material is generally used in the form of a finely divided powder. On the other hand, if the hydrogenation is carried out with immobile catalyst phase and the catalyst is used in the form of a fixed-bed catalyst, for example in a bottoms or trickle reactor, moldings are used rather as support materials. Such shaped articles may be in the form of spheres, tablets, cylinders, hollow cylinders, Raschig rings, strands, calipers, stars, spirals, etc. having a size (dimension of the longest dimension) of about 1 to 30 mm. In addition, the carriers can be present in the form of monoliths, as described, for example, in DE-A-19642770. Furthermore, the carriers can be used in the form of wires, sheets, grids, nets, fabrics and the like. The amount of catalyst to be used depends inter alia on its mode of use and can be determined by a person skilled in the individual case. In general, the ruthenium-containing hydrogenation catalyst may be used in an amount of 0.01 to 20% by weight, preferably 0.1 to 10% by weight, and more preferably 0.1 to 5% by weight, based on the weight of to be hydrogenated compound IX used. The stated amount of catalyst refers to the amount of active metal, ie the ruthenium content of the catalyst.

The reaction temperature is preferably 80 to 200 ⁰ C, particularly preferably 100 to 200 ⁰ C and in particular 100 to 180 ° C.

The reaction is preferably carried out at a pressure of 50 to 350 bar, particularly preferably from 80 to 300 bar, more preferably from 100 to 300 bar, in particular from 150 to 300 bar and especially from 170 to 270 bar.

The pressure can be built up either by hydrogen alone or by a mixture of hydrogen with an inert gas such as nitrogen, argon or carbon dioxide. If a mixture of hydrogen and inert gas is used, the partial pressure of hydrogen must of course be so high that the hydrogenation of compound IX can succeed. Preferably, the partial pressure of hydrogen in the mixture is at least 50%, more preferably at least 70% and in particular at least 80% of the total pressure. Preferably, the pressure is built up solely by hydrogen.

The reaction pressure as well as the reaction temperature depend, inter alia, on the activity and amount of the ruthenium catalyst used and can be determined on a case-by-case basis by a person skilled in the art.

Hydrogen is used in molar excess, based on the compound IX to be hydrogenated. The molar ratio of hydrogen used to the compound used is preferably 1X 500: 1 to 10: 1, particularly preferably 100: 1 to 10: 1 and in particular 50: 1 to 10: 1. The pressures given above refer to the pressure prevailing at the beginning of the reaction. This can fall, especially when carrying out the process C in batch mode in the course of the reaction, for example, to the extent that hydrogen is consumed. If the pressure drop is at most 20%, preferably at most 10% and especially at most 5% of the initial pressure, the pressure need not be set again to the value of the initial pressure. Of course, however, it can be brought to the value of the initial pressure or even to an even higher pressure, for example by repressing hydrogen and / or inert gas, preferably hydrogen, optionally in admixture with inert gas.

The hydrogenation is preferably carried out in a suitable solvent. Suitable solvents are those which are inert under the reaction conditions, d. H. neither react with the starting material or product nor be changed themselves. In particular, suitable solvents are not self-hydrogenated under the hydrogenation conditions. Preferably, the solvents are saturated, i. they contain no C-C double bonds. Suitable solvents include alkanes, especially Cs-Cio alkanes, such as pentane, hexane, heptane, octane, nonane, decane and isomers thereof, cycloalkanes, in particular Cs-Cs-cycloalkanes, such as cyclopentane, cyclohexane, cycloheptane or cyclooctane, open-chain and cyclic ethers, such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, ketones, such as acetone or ethyl methyl ketone, alcohols, in particular C 1 -C 3 -alkanols, such as methanol, ethanol, n-propanol or isopropanol , and also carboxylic acids, such as acetic acid and propionic acid. Also suitable are mixtures of the abovementioned solvents and mixtures thereof with water. Preference is given to polar solvents, such as the abovementioned cyclic ethers, in particular tetrahydrofuran or 1,4-dioxane, the abovementioned ketones, alcohols, carboxylic acids, mixtures thereof or mixtures with water. Specially used is aqueous or nonaqueous acetone, ethanol or methanol in pure form or in a mixture with water or acetic acid, acetic acid in the form of glacial acetic acid or in the form of aqueous acetic acid or especially tetrahydrofuran.

The hydrogenation of the process C can be configured both continuously and discontinuously.

The hydrogenation in the batch mode is usually carried out by initially introducing the compound IX and the catalyst in the solvent, bringing the reaction mixture to the desired temperature and then starting with the introduction of hydrogen. Work up is generally as described below. If the hydrogenation is designed as a continuous process, the exact procedure depends on the type of catalyst used and in particular on whether it is mobile (eg as suspended particles) or immovable (ie as a fixed bed catalyst) in the reactor. Suitable reactors for the use of mobile catalyst phases are continuous slurry reactors, such as continuous stirred tanks, fluidized bed reactors, fluidized bed reactors and bubble column reactors. Suitable fixed bed reactors are, for example, bottom and trickle reactors. The reaction is usually carried out according to the usual procedure for the respective reactor for three-phase reactions.

After completion of the hydrogenation, the catalyst and the solvent are usually removed. The heterogeneous catalyst is preferably separated by filtration or by sedimentation and removal of the upper, product-containing phase. Other separation methods for removing solids from solutions, such as centrifugation, are also suitable for removing the heterogeneous catalyst. The removal of homogeneous catalysts is carried out by conventional methods for the separation of in-phase mixtures, for example by chromatographic methods. Optionally, it may be necessary to deactivate the catalyst prior to removal. This can be done by conventional methods, for example by washing the reaction solution with protic solvents, e.g. with water or with C 1 -C 3 -alkanols, such as methanol, ethanol, propanol or isopropanol, which are, if necessary, basic or acidic.

If desired, the product obtained can be purified by conventional methods, e.g. B. by distillation.

The compounds IX used in process B, step (a) or in process C are either known, in some cases even commercially available (such as triphenylphosphine oxide), or can be prepared by processes known per se. Thus, for example, commercially available phenyl-substituted phosphines, such as triphenylphosphine, DIOP, chiraphos and the like, can be converted into the corresponding phosphine oxide, for example by oxidation with air, pure oxygen or Hydrogen peroxide. A step-by-step construction of compounds IX in which R '"is an alkyl radical is based on diphenylphosphine chlorides substituted by x radicals R ¹ , which are coupled with corresponding di-, tri-, tetra- or pentachloroalkanes in the presence of sodium. The subsequent oxidation of the phosphorus, for example with air, oxygen or hydrogen peroxide, gives the compound IX.

The following statements on suitable and preferred compounds and radicals of the formulas I, II, III, IV, V, VI, VII, VIII, IX, X and Xl apply both on their own and in particular in combination with one another and apply to all three fiction, according to methods A, B and C.

In compounds I, R preferably represents a radical of the formula II. Accordingly, R 'in compound V and R "in compound VII likewise preferably represent a radical of the formula II. Accordingly, R' in the formula IX is preferably a radical of the formula X. ,

Alternatively, in compounds I R is preferably a radical of the formula XII

# - (CR ⁹ R ¹⁰ ) _m - ( ^CR13R14 ) - ( ^{CR11 R12} ) _n - (XU) wherein

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² independently of one another are H, methyl or ethyl,

m and n are independently 0, 1, 2 or 3;

R ¹³ and R ¹⁴ independently of one another are H, methyl, ethyl, -CH 2 -OR ⁷ , in which R ⁷ is defined as above, or a radical of the formula XIII

wherein R ¹ , x and # are as defined above.

Accordingly, R 'in compounds V is preferably a radical of the formula XIV # - (CR ⁹ R ¹⁰ ) _m - ( ^CR15R16 ) - ( ^{CR11 R12} ) _n (XIV) wherein

R ¹ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , m, n, x and # are as defined in formula XII;

Z is halogen; and

R ¹⁵ and R ¹⁶ independently of one another are H, methyl, ethyl, -CH 2 -OR ⁷ , in which R ⁷ is defined as above, or a radical of the formula XV

wherein R ¹ , Z, x and # are as defined above.

Accordingly, R "in compounds VII preferably represents a radical of the formula XVI

# - (CR ⁹ R ¹ ») _m - (CR ¹⁷ R") - (CR »R ¹² )" - Rx (XVI) wherein

R ¹ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , m, n, x and # are as defined in formula XII; and

R ¹⁷ and R ¹⁸ independently of one another are H, methyl, ethyl, -CH 2 -OR ⁷ , in which R ⁷ is defined as above, or a radical of the formula XVII

wherein R ¹ , x and # are as defined above.

Accordingly, R '' in compounds IX preferably represents a radical of the formula XVIII

# - (CR ⁹ R ¹⁰ ) _m - (CR ¹⁹ R ²⁰ ) - (CR ¹¹ R ¹² ) _n (XVI II) wherein

R ¹⁹ and R ²⁰ independently of one another are H, methyl, ethyl, -CH 2 -OR ⁷ , in which R ⁷ is defined as above, or a radical of the formula XIX

wherein R ¹ , x and # are as defined above.

In a preferred embodiment, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ^{20 are} H and the sum of m and n is 0, 1, 2 or 3.

In an alternatively preferred embodiment, m is 0, n is 1, R ¹¹ , R ¹³ , R ¹⁵ , R ¹⁷ and R ¹⁹ are H and R ¹² , R ¹⁴ , R ¹⁶ , R ¹⁸ and R ²⁰ are methyl or ethyl and especially methyl. This embodiment encompasses both the pure threo isomers, the pure erythro isomers, and mixtures thereof. In an alternatively preferred embodiment, R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} H; m and n for 1;

R ^{13 is} a radical of formula XIII; R ^{14 is} H, methyl, ethyl or a radical of formula XIII; R ^{15 is} a radical of the formula XV; R ^{16 is} H, methyl, ethyl or a radical of the formula XV; R ^{17 is} a radical of the formula XVII; R ^{18 is} H, methyl, ethyl or a radical of the formula XVII; R ^{19 is} a radical of formula XIX; and

R ^{20 is} H, methyl, ethyl or a radical of the formula XIX.

In an alternatively preferred embodiment, R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} H; m and n for 1;

R ¹³ , R ¹⁵ , R ¹⁷ and R ^{19 are} H, methyl or ethyl; and R ¹⁴ , R ¹⁶ , R ¹⁸ and R ^{20 are} methyl or ethyl.

R ¹ is preferably C ¹ -C ₄ -alkyl, C ¹ -C ₄ -hydroxyalkyl, C ¹ -C ₄ -haloalkyl or halogen.

Z is preferably Cl.

x is preferably 0.

Particularly preferred compounds I are selected from compounds of the formulas 1.1, I.2, I.3 and I.4

wherein R ¹ and x are as defined above, o is 1, 2, 3 or 4, R ^{α is} H, methyl, ethyl or a radical of formula XIII, R ^{β is} H, methyl or ethyl and R ^{γ is} Methyl or ethyl.

Accordingly, particularly preferred compounds V are selected from compounds V.1, V.2, V.3 and V.4

wherein R ¹ , R ^α , R ^β , R ^γ , x and o have the meanings given above and Z is halogen.

Accordingly, particularly preferred compounds VII are selected from compounds VII.1, VII.2, VII.3 and VII.4

wherein R ¹ , R ^α , R ^β , R ^γ , x and o have the meanings given above.

Accordingly, particularly preferred compounds IX are selected from compounds IX.1, IX.2, IX.3 and IX.4

wherein R ¹ , R ^α , R ^β , R ^γ , x and o have the meanings given above.

In compounds 1.4, V.4, VII.4 and IX.4 R is ^ß preferably H and R ^γ is methyl or ethyl, or R ^ß is preferably methyl and R ^γ is methyl or ethyl.

More preferred compounds I are compounds of formula 1.1. Accordingly, more preferred compounds V are those of the formula V.1, more preferred compounds VII are those of the formula VI 1.1 and more preferred compounds IX are those of the formula IX.1.

In the abovementioned compounds 1.1 to 1.3, V.1 to V.3, VII.1 to VII.3 and IX.1 to IX.3, x is preferably 0. Accordingly, an even more preferred compound I is tricyclohexylphosphine, ie the processes A and B according to the invention are used in particular for the preparation of tricyclohexylphosphine. Correspondingly, the compound V used is in particular a tricyclohexylphosphine dihalide, in particular tricyclohexylphosphine dichloride, as compound VII, in particular tricyclohexylphosphine oxide, and as compound IX (also in process C), in particular triphenylphosphine oxide.

The processes according to the invention allow the preparation of compounds I, such as tricyclohexylphosphine, or of hydrohalides thereof in a high yield in a few reaction steps and using simple and inexpensive reactants. In the case of the production of tricyclohexylphosphine, they allow to start from triphenylphosphine oxide, a large-scale by-product of the Wittig reaction in the synthesis of vitamin A and carotenoids.

The invention will now be explained in more detail by the following, non-limiting examples.

Examples:

1. Hydrogenation of triphenylphosphine oxide

A mixture of triphenylphosphine oxide (707 g, 2.54 mol) and a suspension of ruthenium (IV) oxide hydrate (supported on alumina) (140 g, containing 3 g of ruthenium) in tetrahydrofuran (2 l) was stirred at 120 to Hydrogenated 150 ⁰ C and a hydrogen pressure of 250 bar. After cooling to room temperature, the catalyst was filtered off and the filtrate was freed from the solvent under reduced pressure. Distillation of the residue at 200 to 210 ^° C. (1 mbar) gave 722 g (96% of theory) of tricyclohexylphosphine oxide as a white solid.

2. Reaction of tricyclohexylphosphine oxide to tricyclohexylphosphine hydrochloride and tricyclohexylphosphine

The apparatus used was a 250 ml flask with Teflon blade stirrer, thermometer, non-immersed gas inlet tube with rotameter and overpressure protection (0.1 bar), a reflux condenser with cryostat and a downstream dry ice condenser and a NaOH wash tower. The reflux condenser was cooled to -15 ° C. To the flask was charged 8.0 g (0.027 mol) of tricyclohexylphosphine oxide in 60 ml of anhydrous toluene at room temperature, and phosgene introduction was started. The initially clear, colorless solution immediately became cloudy and it began an exothermic reaction, which could be controlled by throttling the phosgene so that the temperature of the reaction mixture did not exceed 38 ° C. In addition, one sat Gas evolution. Phosgene injection was continued until gas evolution ceased (11.1 g, 0.1 12 moles of phosgene). Subsequently, the reaction mixture was stirred for a further 30 minutes during which the temperature dropped to 25 ° C. To remove excess phosgene was heated under nitrogen inlet 240 minutes at 40 ⁰ C and then further introduced overnight at room temperature to completely remove phosgene nitrogen. After addition of 50 ml of toluene and stirring for 30 minutes, the contents of the flask (130 g) were transferred under argon in a glove box into a mini-autoclave and the autoclave was rinsed twice with 150 bar of nitrogen and then twice with 150 bar of hydrogen. The reaction mixture was heated to 160 ^° C. with stirring and 100 bar of hydrogen were injected. After 48 hours, during which the pressure dropped to 97 bar, the mixture was cooled and vented. The resulting white flocculent precipitate was filtered off under argon and washed twice with 10 ml of toluene. Removal of the solvent under reduced pressure gave 7.4 g (86% of theory) of tricyclohexylphosphine hydrochloride as a white solid.

³¹ P-NMR ( ¹ H-coupled) (145 MHz, toluene-D ₈ ): δ = 28.00 (d, J _PH = 440 Hz).

Elemental analysis (dihydrochloride): C18H35CI2P Calculated: C, 60.8; H, 10.5; P, 8,7. Found: C, 61, 1; H, 10.2; P, 8,4.

To convert the tricyclohexylphosphine hydrochloride to the free base, 40% aqueous sodium hydroxide was added to a portion of the hydrochloride, and the resulting free base was extracted from the aqueous phase with toluene. The yield of free tricyclohexylphosphine was> 90% of theory, based on the amount of hydrochloride used.

Another portion of the hydrochloride was suspended in toluene for conversion to the free base and the suspension was heated to reflux for 40 hours. The solvent was separated by distillation and the residue was distilled in vacuo. The yield of free tricyclohexylphosphine was> 90% of theory, based on the amount of hydrochloride used.

Claims

claims

1. Process for the preparation of compounds of the formula I.

wherein

R is a radical of the formula II

carries and also 1 to 4 substituents of the formula IV

can carry;

X and Y independently represent O or NR ⁸ ;

each R ¹ is independently _Ci-C4 -alkyl, _{Ci-C4-haloalkyl,} Ci-C ₄ hydroxyalkyl, C ₃ -

Cio-cycloalkyl, Cs-do-halocycloalkyl, halogen, OR ² or COR ³ ;

R ^{2 is} H or C 1 -C ₄ alkyl; R ^{3 is} H, C 1 -C ₄ alkyl, OR ⁴ or NR ⁵ R ⁶ ;

R ⁴ , R ⁵ and R ⁶ independently of one another are H or C 1 -C ₄ -alkyl;

R ⁷ is H, -C ₄ -alkyl or C ₂ -C ₄ hydroxyalkyl; or in the event that two substituents of the formula IV are bonded to the same or to two adjacent carbon atoms of the alkyl radical, two radicals R ^{7 can} also together form a linear or branched alkylene group having 1 to 6 carbon atoms;

R ⁸ is H, Ci-C ₄ alkyl or C ₂ -C ₄ hydroxyalkyl group;

each x is independently 0 or an integer from 1 to 3;

a is 2, 3 or 4;

b is 0 or an integer from 1 to 10; and

# denotes the point of attachment to the rest of the molecule;

or hydrohalides thereof, comprising the following step:

Reaction of compounds of the formula V

wherein

and may also carry 1 to 4 substituents of the formula IV; and

Z is halogen;

with hydrogen at a pressure of 10 to 300 bar.

2. The method of claim 1, wherein the pressure is 50 to 200 bar.

3. The method according to any one of the preceding claims, wherein the reaction is carried out in the presence of a base.

4. The method of claim 3, wherein the base comprises at least one amine of the formula NR ^a R ^b R ^c , wherein R ^a , R ^b and R ^c independently of one another are H, C 1 -C 10

₄ alkyl are alkyl, Ci-Cio-hydroxyalkyl, C ₃ -Cio cycloalkyl, aryl or aryl-Ci-C.

5. The method according to any one of claims 1 or 2, wherein the reaction product of the compound of formula V is then neutralized with hydrogen and subsequently treated with a base or thermally treated.

6. The method according to any one of the preceding claims, wherein the compound of formula V is obtained by reacting a compound of formula VII

wherein

R "is a radical of formula II or a linear or branched alkyl radical having 1 to 8 carbon atoms, the 1, 2, 3 or 4 radicals of the formula VIll l)

and may also carry 1 to 4 substituents of the formula IV; and

R ¹ , x and # are as defined in claim 1;

reacted with a halogenating agent.

7. The method of claim 6, wherein the halogenating agent is selected from phosgene, phosphorus trichloride, thionyl chloride and oxalyl chloride.

8. A process for the preparation of compounds of formula I as defined in

Claim 1 or hydrohalides thereof, comprising the following steps:

(a) hydrogenation of compounds of formula IX

wherein

R '"for a radical of the formula X.

and may also carry from 1 to 4 substituents of formula IV as defined in claim 1; and

R ¹ , x and # are as defined in claim 1;

to obtain compounds of formula VII as defined in claim 6;

(b) reacting the compounds of formula VII obtained in step (a) with a halogenating agent to obtain compounds of formula V as defined in claim 1;

(c) reacting the compounds of formula V obtained in step (b) with a reducing agent to give compounds I or a hydrohalide thereof.

The process of claim 8, wherein the hydrogenation in step (a) comprises reacting compounds IX with hydrogen in the presence of a hydrogenation catalyst.

A process according to any one of claims 8 or 9, wherein the hydrogenation catalyst contains at least one Group VIII metal.

1 1. The method of claim 10, wherein the Group VIII metal is selected from ruthenium, cobalt, rhodium, nickel, palladium and platinum.

The process of claim 11, wherein the Group VIII metal is ruthenium.

13. The method of claim 12, wherein the ruthenium-based hydrogenation catalyst is selected from ruthenium (IV) oxide, its hydrate, ruthenium (VIII) oxide, its hydrate, elemental ruthenium and elemental Ruthe- nium in admixture with at least one metal of Groups VIIb, VIII, Ib or IIb.

14. The method according to any one of claims 8 to 13, wherein the halogenating agent used in step (b) is selected from phosgene, phosphorus trichloride, thiophyl chloride and oxalyl chloride.

15. The method according to any one of claims 8 to 14, wherein the reducing agent used in step (c) is selected from hydrogen, metals of the first to fifth main group, subgroup elements which are selected from Sc, Y, La, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Co, Ni and Zn, boron, silicon, arsenic, selenium, tellurium, lithium aluminum hydride, phosphorus and carbon.

16. The method of claim 15, wherein the reducing agent used in step (c) is selected from hydrogen, sodium, potassium, magnesium, aluminum, iron, lithium aluminum hydride and silicon.

17. The method according to claim 16, wherein the reduction in step (c) is carried out by reacting the compounds V with hydrogen as a reducing agent at a pressure of 10 to 300 bar.

18. A process for the preparation of compounds of the formula VII as defined in claim 6, comprising the following step:

Reacting compounds of formula IX as defined in claim 8 with hydrogen in the presence of a ruthenium-based hydrogenation catalyst.

19. The process according to claim 18, wherein the ruthenium-based hydrogenation catalyst is selected from ruthenium (IV) oxide, its hydrate, ruthenium (VIII) oxide, its hydrate, elemental ruthenium and elemental ruthenium in admixture with at least one metal of groups VIIb , VIII, Ib or IIb, wherein the hydrogenation catalyst is supported on alumina.

20. The method according to any one of claims 18 and 19, wherein the reaction is carried out at a pressure of 50 to 350 bar.

21. The method according to any one of claims 18 to 20, wherein the reaction takes place at a temperature of 80 to 200 ⁰ C.

22. The method according to any one of claims 1 to 21, wherein R, R 'and R "are a radical of the formula II and R'" is a radical of the formula X.

23. The method according to any one of claims 1 to 21, wherein R is a radical of the formula XII

# - (CR »R ¹⁰ ) _m - (CR ¹³ R" MCR "R ¹² ) _n - (XII)

R 'is a radical of the formula XIV

# - (CR ⁹ R ¹⁰ ) _m - (CR ¹⁵ R ¹⁶ ) - (CR ¹¹ R ¹² ) _n (XIV)

R "is a radical of the formula XVI

# - (CR ⁹ R ¹⁰ ) _m - ( ^CR17R18 ) - ( ^{CR11 R12} ) _n (XVI)

R '"is a radical of the formula XVIII

(XVIII) wherein

m and n are independently 0, 1, 2 or 3;

R ¹³ and R ^{14 are} independently H, methyl, ethyl, -CH 2 -OR ⁷ , wherein R ^{7 is} as defined in claim 1, or a radical of formula XIII

R ¹⁵ and R ¹⁶ independently represent H, methyl, ethyl, -CH 2 -OR ⁷ , wherein R ^{7 is} as defined in claim 1, or a radical of the formula XV

R ¹⁷ and R ^{18 are} independently H, methyl, ethyl, -CH 2 -OR ⁷ , wherein R ^{7 is} as defined in claim 1, or a radical of formula XVII

R ¹⁹ and R ^{20 are} independently H, methyl, ethyl, -CH ₂ -OR ⁷ , wherein R ^{7 is} as defined in claim 1, or a radical of formula XIX

and

R ¹ , Z and x are as defined in claim 1.

24. The method of claim 23, wherein R ^9, R ^10, R ^11, R ^12, R ^13, R ^14, R ^15, R ^16, R ^17, R ^18, R ¹⁹ and R ²⁰ are H and the sum of m and n are 0, 1, 2 or 3.

The method of claim 23, wherein m is O, n is 1, R ¹¹ , R ¹³ , R ¹⁵ , R ¹⁷ and R ^{19 are} H and R ¹² , R ¹⁴ , R ¹⁶ , R ¹⁸ and R ²⁰ represent methyl or ethyl.

The process of claim 23 wherein R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} H; m and n are 1;

R ^{13 is} a radical of formula XIII;

R ^{14 is} H, methyl, ethyl or a radical of formula XIII;

R ^{15 is} a radical of the formula XV; R ^{16 is} H, methyl, ethyl or a radical of formula XV;

R ^{17 is} a radical of formula XVII;

R ^{18 is} H, methyl, ethyl or a radical of formula XVII;

R ^{19 is} a radical of formula XIX; and

R ^{20 is} H, methyl, ethyl or a radical of the formula XIX.

27. The method of claim 23, wherein R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} H; m and n are 1;

28. The method according to any one of the preceding claims, wherein x is 0.